SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

Manseldem 60/1000mg Film-coated Tablets

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each film-coated tablet contains 60mg Codeine Phosphate Hemihydrate and 1000mg Paracetamol

Excipient with known effect: Each film-coated tablet contains 5.85mg lecithin soya (E322).

For the full list of excipients, see section 6.1

3 PHARMACEUTICAL FORM

Film-coated tablets

Manseldem Film-coated tablets are white, oval, 10.7 x 21.4mm, biconvex tablets, marked ’10 6’ on one side with a score line on the other side and side scores.

The score line is only to facilitate breaking for ease of swallowing and not to divide into equal doses.

4    CLINICAL PARTICULARS

4.1    Therapeutic indications

For the relief of moderate to severe pain in adults and adolescents 16 years and older.

Codeine is indicated in patients 16 years and older for the treatment of acute moderate pain which is not considered to be relieved by other analgesics such as paracetamol or ibuprofen (alone).

4.2 Posology and method of administration

Posology

The duration of treatment should be limited to 3 days and if no effective pain relief is achieved the patients/carers should be advised to seek the views of a physician.

This presentation is reserved for use in adults and in adolescents over 50kg of body weight aged 16 years and above.

Adults over 18 years: One tablet not more frequently than every 4 hours, up to a maximum of 4 tablets in any 24 hour period.

Adolescents over 50kg of body weight aged 16 years and above:

One tablet not more frequently than every 6 hours, up to a maximum of 4 tablets in any 24 hour period.

Maximum daily dose:

•    The maximum daily dose of Paracetamol must not exceed 4000 mg.

•    Maximum single dose is 1000 mg (1 tablet).

Elderly: As adults, however a reduced dose may be required. See warnings.

Renal insufficiency

In case of renal insufficiency the dose should be reduced:

Glomerulal filtration	Dose
10 - 50 ml/min	One Manseldem 60 mg / 1000 mg tablet every 6 hours*
< 10 ml/min	One Manseldem 60 mg / 1000 mg tablet every 8 hours*

* Manseldem 30 mg / 500 mg tablets are available for the above cases.

Hepatic insufficiency

Paracetamol should be used with caution in the presence of hepatic insufficiency.

Chronic alcoholism

Chronic alcohol consumption may lower the paracetamol toxicity threshold. In these patients, the length of time between two doses should be a minimum of 8 hours. 2 g paracetamol per day should not be exceeded.

Paediatric population: Manseldem should not be used in children below the age of 16 due to the risk of paracetamol poisoning. Also, codeine should not be used in children below the age of 16 years because of the risk of opioid toxicity due to the variable and unpredictable metabolism of codeine to morphine (see sections 4.3 and 4.4).

Method of administration

Manseldem Film-coated tablets are for oral use.

4.3 Contraindications

-    Hypersensitivity to the active substances, soya or peanut or to any of the excipients listed in section 6.1

-    In all paediatric patients (0-18 years of age) who undergo tonsillectomy and/or adenoidectomy for obstructive sleep apnoea syndrome due to an increased risk of developing serious and life-threatening adverse reactions (see section 4.4).

-    In women during breastfeeding (see section 4.6).

-    In patients for whom it is known they are CYP2D6 ultra-rapid metabolisers.

Conditions where morphine and opioids are contraindicated e.g.:

-    Acute asthma

-    Respiratory depression

-    Acute alcoholism

-    Hepatic failure

-    Head injuries

-    Raised intra-cranial pressure

-    Following biliary tract surgery

-    Monoamine oxidase inhibitor therapy, concurrent or within 14 days.

4.4 Special warnings and precautions for use

Administration of doses higher than that recommended poses a risk of severe liver damage. Antidote treatment should be administered as quickly as possible (see section 4.9).

Tolerance and also physical and psychological dependence can occur with chronic administration.

Abrupt discontinuation following long-term, high-dose, incorrect use of analgesics may lead to headaches, fatigue, muscle pain, nervousness and autonomic symptoms. These withdrawal symptoms resolve within a few days. Until this time, further intake of analgesics should be avoided and not restarted without medical advice.

Where analgesics are used long-term (> 3 months) with administration every two days or more frequently, headache may develop or worsen. Headache induced by overuse of analgesics (MOH - medication-overuse headache) should not be treated by dose increase. In such cases, the use of analgesics should be discontinued in consultation with the doctor.

Paracetamol/codeine should be used with caution in patients with:

-    opioid-dependent patients

-    hypothyroidism

-    prostatic hypertrophy

-    adrenocortical insufficiency

-    severe hepatic haemolytic anaemia

Paracetamol/codeine should be used with the outmost caution and in reduced doses in patients with:

-    severely impaired kidney function.

-    impaired liver function or alcoholism.

-    malnourished or dehydrated patients.

CYP2D6 metabolism

Codeine is metabolised by the liver enzyme CYP2D6 into morphine, its active metabolite. If a patient has a deficiency or is completely lacking this enzyme an adequate analgesic effect will not be obtained. Estimates indicate that up to 7% of the Caucasian population may have this deficiency. However, if the patient is an extensive or ultra-rapid metaboliser there is an increased risk of developing side effects of opioid toxicity even at commonly prescribed doses. These patients convert codeine into morphine rapidly resulting in higher than expected serum morphine levels.

General symptoms of opioid toxicity include confusion, somnolence, shallow breathing, small pupils, nausea, vomiting, constipation and lack of appetite. In severe cases this may include symptoms of circulatory and respiratory depression, which may be life-threatening and very rarely fatal.

Estimates of prevalence of ultra-rapid metabolisers in different populations are summarized below:

African/Ethiopian	29%
African American	3.4% to 6.5%
Asian	1.2% to 2%
Caucasian	3.6% to 6.5%
Greek	6.0%
Hungarian	1.9%
Northern European	1%-2%

Post-operative use in children

There have been reports in the published literature that codeine given post-operatively in children after tonsillectomy and/or adenoidectomy for obstructive sleep apnoea, led to rare, but life-threatening adverse events including death (see also section 4.3). All children received doses of codeine that were within the appropriate dose range; however there was evidence that these children were either ultra-rapid or extensive metabolisers in their ability to metabolise codeine to morphine.

Children with compromised respiratory function

Codeine is not recommended for use in children in whom respiratory function might be compromised including neuromuscular disorders, severe cardiac or respiratory conditions, upper respiratory or lung infections, multiple trauma or extensive surgical procedures. These factors may worsen symptoms of morphine toxicity.

Care should be observed in administering the product to any patient whose condition may be exacerbated by opioids, particularly the elderly, who may be sensitive to their central and gastro-intestinal effects, those on concurrent CNS depressant drugs, those with prostatic hypertrophy and those with inflammatory or obstructive bowel disorders. Care should also be observed if prolonged therapy is contemplated.

Patients should be advised not to exceed the recommended dose and not take other paracetamol containing products concurrently.

The risk-benefit of continued use should be assessed regularly by the prescriber.

4.5 Interaction with other medicinal products and other forms of interaction

The following combinations with Manseldem should be avoided: quinidine.

The following combinations with Manseldem may require dose adjustment: neuroleptics, antidepressants, warfarin, enzyme-inducing medications such as certain antiepileptics (phenytoin, phenobarbital, carbamazepine), rifampicin and St John's wort (Hypericum perforatum), probenecid, metoclopramide, cholestyramine and chloramphenicol.

Simultaneous use of alcohol should be avoided.

Codeine

Pharmacokinetic interactions:

Codeine is probably active through the codeine being O-demethylated to morphine via the enzyme CYP2D6. This bioactivation is inhibited by certain medications, e.g. quinidine, terbinafine, certain antidepressants and neuroleptics, etc. These drugs therefore counter the effect of codeine. This interaction has been documented in studies on healthy trial subjects and/or pilot studies on patients.

Direct studies have been performed with quinidine, which is a very strong inhibitor of CYP2D6, and this combination should therefore be avoided.

Neuroleptics and antidepressants also have an inhibiting effect on CYP2D6, which means that these combinations may require a dose adjustment.

Enzyme-inducing medications such as rifampicin, barbiturates, several antiepileptics, St John's wort (Hypericum perforatum), etc. can produce reduced plasma concentrations of morphine (see also interaction with paracetamol below).

Paracetamol

Pharmacodynamic interactions:

The anticoagulant effect of warfarin and other coumarins may be enhanced by regular use of paracetamol with increased risk of bleeding. The effect may occur already at daily doses of 2000 mg after 3 days. Occasional doses have no significant effect on bleeding tendency. Increased monitoring of INR values should be done during the duration of the combination and after its discontinuation.

Pharmacokinetic interactions:

Use of substances that induce liver enzymes, such as carbamazepine, phenytoin, phenobarbital, rifampicin and St John’s wort (Hypericum perforatum) can increase the hepatotoxicity of paracetamol due to increased and more rapid formation of toxic metabolites. Therefore, caution should be taken in case of concomitant use of enzyme inducing substances.

Probenecid nearly halves the clearance of paracetamol by inhibiting its conjugation with glucuronic acid. This probably means that the dose of paracetamol can be halved when being given at the same time as probenecid.

Concurrent intake of medicinal products that accelerate gastric emptying, such as metoclopramide or domperidone, accelerates the absorption and onset of effect of paracetamol.

The absorption of paracetamol is reduced by cholestyramine. Cholestyramine should not be given within one hour if maximum analgesic effect is to be obtained.

Paracetamol may affect the pharmacokinetics of chloramphenicol. Therefore an analysis of chloramphenicol in plasma is recommended in the event of combination treatment with chloramphenicol for injection.

4.6 Fertility, pregnancy and lactation

Pregnancy

Manseldem should be used with caution during pregnancy since codeine metabolites cross the placenta.

Respiratory depression has been reported in neonates in connection with the use of codeine during childbirth.

A large amount of data on pregnant women indicate neither malformative, nor feto/neonatal toxicity. Paracetamol can be used during pregnancy if clinically needed however it should be used at the lowest effective dose for the shortest possible time and at the lowest possible frequency.

Abstinence symptoms have been reported in babies born to mothers who have regularly used paracetamol/codeine during pregnancy

Breastfeeding

This product is contraindicated during breastfeeding due to the codeine component (see section 4.3).

Paracetamol is excreted in breast milk but not in a clinically significant amount.

Codeine should not be used during breastfeeding (see section 4.3).

At normal therapeutic doses codeine and its active metabolite may be present in breast milk at very low doses and is unlikely to adversely affect the breast fed infant. However, if the patient is an ultra-rapid metaboliser of CYP2D6, higher levels of the active metabolite, morphine, may be present in breast milk and on very rare occasions may result in symptoms of opioid toxicity in the infant, which may be fatal.

4.7 Effects on ability to drive and use machines

Patients should be advised not to drive or operate machinery if affected by dizziness or sedation.

This medicine can impair cognitive function and can affect a patient’s ability to drive safely. This class of medicine is in the list of drugs included in regulations under 5a of the Road Traffic Act 1988. When prescribing this medicine, patients should be told:

•    The medicine is likely to affect your ability to drive

•    Do not drive until you know how the medicine affects you

•    It is an offence to drive while under the influence of this medicine

•    However, you would not be committing an offence (called ‘statutory defence’) if:

-    The medicine has been prescribed to treat a medical or dental problem and

-    You have taken it according to the instructions given by the prescriber and in

the information provided with the medicine and

-    It was not affecting your ability to drive safely.

4.8 Undesirable effects

Codeine can produce typical opioid effects including constipation, nausea, vomiting, dizziness, light-headedness, confusion, drowsiness and urinary retention. The frequency and severity are determined by dosage, duration of treatment and individual sensitivity. Tolerance and dependence can occur, especially with prolonged high dosage of codeine.

• Regular prolonged use of codeine is known to lead to addiction and tolerance. Symptoms of restlessness and irritability may result when treatment is then stopped.

• Prolonged use of a painkiller for headaches can make them worse.

The frequency of undesirable effects is classified as follows: Very common (>1/10); common (>1/100 to <1/10); uncommon (>1/1,000 to <1/100); rare (>1/10,000 to <1/1,000); very rare (<1/10,000), not known (cannot be estimated from the available data).

Undesirable effects

Blood and lymphatic system
disorders	Thrombocytopaenia, haemolytic
Rare	anaemia, agranulocytosis,
	leukopaenia.
Very rare	Pancytopaenia.
Immune system disorders

Rare	Allergic reactions.
Psychiatric disorders Rare	Sleep disturbances.
Nervous system disorders Common	Drowsiness, headache.
Uncommon	Dizziness.
Eye disorders Uncommon	Disturbances of vision.
Vascular disorders Common	Bouts of perspiration.
Respiratory, thoracic and mediastinal disorders Rare	Breathlessness.
Gastrointestinal disorders Common	Nausea, constipation, vomiting.
Uncommon	Dryness of the mouth.
Hepatobiliary disorders Rare	Hepatotoxicity, liver damage which may lead to liver failure.
Very rare	Acute pancreatitis.
Skin and subcutaneous tissue disorders Rare	Rash, urticaria erythema.

Renal and urinary disorders Very rare	Renal damage (may occur in long-term therapy.)
General disorders and administration site conditions Common	Fatigue.

Very rare cases of serious skin reactions have been reported.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme Website: www.mhra.gov.uk/yellowcard

4.9 Overdose

Codeine

The effects of Codeine overdosage will be potentiated by simultaneous ingestion of alcohol and psychotropic drugs.

Symptoms

Central nervous system depression, including respiratory depression, may develop but is unlikely to be severe unless other sedative agents have been co-ingested, including alcohol, or the overdose is very large. The pupils may be pin-point in size; nausea and vomiting are common. Hypotension and tachycardia are possible but unlikely.

Management

Management should include general symptomatic and supportive measures including a clear airway and monitoring of vital signs until stable. Consider activated charcoal if an adult presents within one hour of ingestion of more than 350 mg or a child more than 5 mg/kg.

Give naloxone if coma or respiratory depression is present. Naloxone is a competitive antagonist and has a short half-life so large and repeated doses may be required in a seriously poisoned patient. Observe for at least 4 hours after ingestion, or 8 hours if a sustained release preparation has been taken.

Paracetamol

Immediate medical advice should be sought in the event of overdosage because of the risk of irreversible liver damage.

Symptoms

Symptoms of Paracetamol overdosage in the first 24 hours are pallor, nausea, vomiting, anorexia and abdominal pain. Liver damage may become apparent 12 to 48 hours after ingestion and this may be manifested in increasing pro-thrombin time, which is a reliable indicator of deteriorating liver function. Abnormalities of glucose metabolism and metabolic acidosis may occur. In severe poisoning, hepatic failure may progress to encephalopathy, haemorrhage, hypoglycaemia, cerebral oedema, coma and death. Acute renal failure with acute tubular necrosis, strongly suggested by loin pain, haematuria and proteinuria, may develop even in the absence of severe liver damage.

Cardiac arrhythmias and pancreatitis have been reported.

Liver damage is likely in adults who have taken 10g or more of Paracetamol. Acute or chronic ingestion of Paracetamol above the recommended dose may lead to liver damage particularly if the patient has risk factors.

Risk Factors

a)    Is on long term treatment with carbamazepine, phenobarbitone, phenytoin, primidone, rifampicin, St John's Wort or other drugs that induce liver enzymes.

Or

b)    Regularly consumes ethanol in excess of recommended amounts.

Or

c)    Is likely to be glutathione deplete e.g. eating disorders, cystic fibrosis, HIV infection, starvation, cachexia.

It is considered that excess quantities of toxic metabolite (usually adequately detoxified by glutathione when normal doses of Paracetamol are ingested), become irreversibly bound to liver tissue.

Management

Immediate treatment is essential in the management of Paracetamol overdose. Despite lack of significant early symptoms, patients should be referred to hospital urgently for immediate attention. Symptoms may be limited to nausea or vomiting and may not reflect the severity of overdose or the risk of organ damage.

Treatment with activated charcoal should be considered if the overdose has been taken within 1 hour. Plasma paracetamol concentrations should be measured at 4 hours or later after ingestion (earlier concentrations are unreliable).

Or any patient who have ingested about 7.5g or more of Paracetamol in the preceding 4 hours should undergo gastric lavage. Plasma paracetamol concentrations should be measured at 4 hours or later after ingestion (earlier concentrations are unreliable).

Treatment with N-Acetylcysteine may be used up to 24 hours after ingestion of paracetamol however, the maximum protective effect is obtained up to 8 hours post indigestion.

If required the patient should be given intravenous-N-acetylcysteine, in line with the established dosage schedule. If vomiting is not a problem, oral methionine may be a suitable alternative for remote areas, outside hospital. General supportive measures must be available.

Management of patients who present with serious hepatic dysfunction beyond 24 hours from ingestion should be discussed with the NPIS or a liver unit.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Codeine, combinations excl. psycholeptics. ATC Code: N02AA59

Paracetamol has both analgesic and antipyretic effects. However, it does not have an anti-inflammatory effect. The mechanism of analgesic action has not been fully determined. The main action of paracetamol is the inhibition of cyclo-oxygenase, an enzyme which is important for the prostaglandin synthesis. Central nervous system cyclo-oxygenase is more sensitive for paracetamol than peripheral cyclo-oxygenase and this explains why paracetamol has an antipyretic and analgesic efficacy. Paracetamol probably produces antipyresis by acting centrally on the hypothalamic heat regulating centre.

Codeine is a centrally acting weak analgesic. Codeine exerts its effect through p opioid receptors, although codeine has low affinity for these receptors, and its analgesic effect is due to its conversion to morphine. Codeine, particularly in combination with other analgesics such as paracetamol, has been shown to be effective in acute nociceptive pain.

Codeine phosphate is used in the treatment of cough and depression effects on CNS. Codeine can potentiate effect of other analgetics.

Codeine is much less potent than morphine and it is inadequate against severe pain even in the largest tolerable doses. It does not cause appreciable respiratory depression but does have antitussive effects. Codeine differs from morphine in that for normal medical use serious dependence is not frequently associated with codeine and large doses produce excitement rather than depression. Codeine has a low affinity to opioid receptors. The analgesic effect of codeine may be due to biotransformation to morphine.

5.2 Pharmacokinetic properties

Paracetamol

Absorption

After oral administration paracetamol is rapidly and almost completely absorbed. Peak plasma concentrations are reached after 30 minutes to 2 hours.

Distribution

Paracetamol is distributed rapidly throughout all tissues. Concentrations are comparable in blood, saliva and plasma. The volume of distribution of paracetamol is approximately 1 l/kg bodyweight. At therapeutic doses protein binding is negligible.

Biotransformation

In adults paracetamol is metabolized in the liver following two major metabolic pathways: glucuronic acid (~60 %) and sulphuric acid (~35 %) conjugates. The latter route is rapidly saturated at doses higher than the therapeutic dose. A minor route, catalyzed by the cytochrome P450, results in the formation of an intermediate reagent (N-acetyl-p-benzoquinoneimine) which under normal conditions of use is rapidly detoxified by glutathione and eliminated in the urine, after conjugation with cystein (~3 %) and mercaptopuric acid. In neonates and children <12 years sulphate conjugation is the main elimination route and glucuronidation is lower than in adults. Total elimination in children is comparable to that in adults, due to an increased capacity for sulphate conjugation.

Elimination

Elimination of paracetamol is essentially through the urine. 90% of the ingested dose is eliminated via the kidneys within 24 hours, predominantly as the glucuronide (60 to 80 %) and the sulphate (20 to 30%) conjugates. Less than 5% is eliminated in unchanged form. The elimination half life is about 2 hours.

In cases of renal or hepatic insufficiency, after overdose, and in neonates the elimination half life of paracetamol is delayed. The maximum effect is equivalent with plasma concentrations.

In cases of severe renal insufficiency (creatinine clearance lower than 10 ml/min) the elimination of paracetamol and its metabolites is delayed.

For elderly patients, the capacity for conjugation is not modified.

Codeine _ phosphate Absorption

Codeine phosphate is absorbed quickly and almost completely from gastrointestinal tract. Maximum plasma concentration is observed after approximately 2 hours.

Distribution

Plasma concentration after administration of single 30 mg codeine phosphate dose is approximately 0,25 pmol/l.

Biotransformation

Codeine phosphate is metabolised in liver. Approximately 10 % of the administered dose is converted to morphine, which is assumed to be responsible for the effect.

Elimination

Elimination half life is 3,5 hours. Codeine phosphate is excreted mainly renally as inactive metabolites. Two thirds of these are excreted in 6 hours. Effect is remained for 4 - 6 hours.

Linearitv/non-linearitv

Codeine phosphate has log-linear kinetics in the elimination phase.

Just under 10 % of the population is unable to convert codeine to morphine, which is why such individuals will not benefit from the codeine content of the tablets.

Elderly patients may metabolise codeine more slowly than younger ones. Dose adjustment may be considered.

5.3 Preclinical safety data

There are no non-clinical data of relevance which are additional to that already included in other sections of the SPC.

6    PHARMACEUTICAL PARTICULARS

6.1    List of excipients

Tablet core:

Povidone K29/32 Magnesium stearate Silica colloidal anhydrous Talc

Sodium croscarmellose Copovidone (25.2-30.8)

Cellulose microcrystalline

Tablet coating:

Hydroxypropylated starch (E1440) Talc

Mannitol

Lecithin soya (E322)

Titanium dioxide (E171)

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

2 years

6.4 Special precautions for storage

This medicinal product does not require any special storage conditions

6.5 Nature and contents of container

White PVC/Aluminium blisters

or white HDPE tablet container with a white LDPE cap

or white HDPE tablet container with a white PP child-resistant screw cap.

Pack Sizes:

PVC/Aluminium blisters: 8, 10, 16, 20, 24, 30, 40, 50 and 100 film-coated tablets Tablet containers: 50 and 100 film-coated tablets Not all pack sizes may be marketed.

6.6 Special precautions for disposal

No special requirements.

MARKETING AUTHORISATION HOLDER

Actavis Group PTC ehf. Reykjavikurvegi 76-78 220 Hafnarfjordur Iceland

8    MARKETING AUTHORISATION NUMBER(S)

PL 30306/0496

9    DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

13/05/2015

10    DATE OF REVISION OF THE TEXT

13/05/2015